Hypertension (or high blood pressure) is a condition which occurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While such "essential" hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been elucidated. Additionally, many patients display the symptoms of high blood pressure in the complete absence of any other sign of disease or disorder.
It is known that hypertension can directly lead to heart failure, renal failure and stroke (brain hemorrhaging). These conditions are capable of causing short-term death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a patient and can lead to long-term death.
The exact cause of essential hypertension is unknown, though a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin, aldosterone system), excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in constricted blood vessels and genetic factors.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus a broad range of .beta.-blockers, vasoconstrictors, renin inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure and brain hemorrhaging. However, the development of atherosclerosis or heart disease due to hypertension over a long period of time remains a problem. This implies that although high blood pressure is being reduced, the underlying cause of essential hypertension is not responding to this treatment.
Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. (See, for example, Kaplan, N.M., Clinical Diabetes, 9, 1-9 (1991), Ferranninni, E., et. al., New England Journal of Medicine, 317. 350-57 (1987), and Shen, D.-C., Journal of Clinical Endocrinology, 66, 580-3 (1988).) Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts to promote vascular cell growth and increase renal sodium retention, among other things. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries; while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby should alleviate hypertension.
Pershadsingh, et al., International Patent Publication No. WO 91/05538, disclose the following antihypertensive thiazolidinediones: ##STR1## where X is a lower alkylidene or a bond; or --HC.dbd.CH--; Y is oxo or imino; Z is oxo or imino; and R.sub.1 is a structurally diverse variable comprised of such groups as ##STR2## with definitions of the remaining variables given in detail in said patent application.
The present invention is directed to a new use for the compounds of formula (I), ##STR3## wherein X is C.dbd.O or CHOH. These compounds have been disclosed in U.S. Pat. No. 5,036,079 as being useful in the treatment of hyperglycemia and hypercholesterolemia, by virtue of blood glucose level lowering properties and blood cholesterol level lowering properties, respectively.
The present invention provides the surprising and beneficial result that these compounds lower plasma insulin levels after administration to a mammalian subject. More particularly, this insulin level lowering effect is independent of the hypoglycemic properties of the compounds of formula (I). Thus, the compounds of formula (I) reduce insulin levels in a hyperinsulinemic, normoglycemic patient without affecting the blood glucose levels in said patient. The term "normoglycemic patient" is defined as a patient having normal glucose levels. This lowering of blood insulin levels results in a reduction of blood pressure in a hypertensive mammal.
The new use of the present invention comprises administration of at least one of the foregoing compounds of formula I to a mammal suffering from hypertension. Said compounds lower blood insulin levels of the suffering mammal thereby alleviating the hypertension.